Bioneex Story with the CEO of 4M Therapeutics
Pablo Lapuerta
Founded in 2021, 4M Therapeutics was started in order to develop new drugs for central nervous system disorders, beginning with bipolar disorder.
“We wanted to solve the problem of lithium, the most effective drug ever developed for bipolar disorder, but a drug that has too many side effects, side effects that don’t relate to its efficacy,” says 4M CEO Pablo Lapuerta.
Lithium is a metal, it has to be given at high doses, and it damages the kidney. 4M believes it can solve the problem by treating bipolar disorder with more potent compounds at much lower doses that don’t contain metal and therefore do not damage the kidney, but that also can provide better safety and efficacy.
4M targets the pathway that lithium affects, the WNT pathway. Age-related decline in WNT protein expression is associated with dementia and Parkinson’s disease.
In the brain, GSK3, CRMP2, and WNT have been linked to cell activities including neurogenesis, synaptic plasticity, and survival. Deficiencies in how these pathways are regulated have been associated with many psychiatric and neurological conditions, including bipolar disorder and Alzheimer’s disease.
“We chose bipolar disorder because the efficacy of lithium is so great and so closely tied to this pathway and it gives us our highest probability of success,” Lapuerta said. “Eventually, we hope to study other conditions like Alzheimer's disease and Parkinson's disease.”
4M identifies and optimizes candidate medicines by examining their effects on pathways in living human brain cells that have been derived from induced pluripotent stem cells.
Lapuerta said its scientific founders have derived IPSCs from people with bipolar disorder and Alzheimer's disease in their labs and have shown that both have problems related to this WNT pathway, problems that lithium addresses. “What we have done as a separate company is we validated their results in brain cells from normal individuals showing that we can affect the same pathway the right way to the same extent as lithium, but at much lower concentrations,” he said.
The company works with contract laboratories that have induced pluripotent stem cells and can grow them into neurons and test the efficacy of 4M’s compounds. 4M already has a compound that has shown the same effects as lithium in human brain cells. “This drug is as effective as lithium at 1/1000th the concentration,” Lapuerta says. “We took the same drug into animal studies and it reduced mania-like behavior just like lithium did and avoided the kidney toxicity of lithium.” The compound, 4MT2001, is an oral medication that can cross the blood brain barrier and be given once a day. It is now in IND-enabling toxicology studies that the company anticipates moving into the clinic in 2025.
4MT2001 is a metabolite of ruboxistaurin, which was originally developed by Eli Lilly to inhibit a certain kinase associated with complications of diabetes. Eli Lilly didn’t know that ruboxistaurin also inhibited a kinase that is the central node of the lithium response. This discovery was made years later by one of 4M’s scientific founders, Dr. Stephen Haggarty, who obtained a patent for this use. As 4M studied ruboxistaurin, they realized that it was metabolized rapidly into another chemical that had better pharmacokinetics and was more than twice as potent. Over 2000 people had already been exposed to this metabolite in clinical trials and the safety supported its development. 4M filed new patent applications based on the metabolite and its superior pharmacokinetics and potency.
“It’s very novel to be able to develop a 20-year-old drug but with patent applications that were dated in 2022 and 2023,” Lapuerta notes.
Lapuerta sees the future as promising. The company has raised $5 million to date and needs to raise $3 million more to fund the IND enabling studies to progress to a point that will support a series A financing by the end of 2024 in order to fund a clinical trial in 2025.
4M has also joined the Bioneex drug candidates marketplace platform in order to extend its network of contacts and give exposure to the company.
“I really like Smbat, and we get along well,” said Lapuerta. “4M is happy to be listed on the Bioneex platform and expand our network.”